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• Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. https://doi.org/10.1136/bmj.b4909. In this post hoc analysis of the ACCORD trial, patients who experienced severe hypoglycemia had a significantly higher risk of all-cause mortality irrespective of allocation to the intensive or standard treatment arm. However, hypoglycemia was the direct cause of death in only one of 451 deaths in the study.
• Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care. 2015;38(2):316–22. https://doi.org/10.2337/dc14-0920. This study retrospectively analyzed the data of insulin-treated patients (10,422 with type 2 diabetes), with a mean follow-up of 4.8 years, demonstrating an association between hypoglycemia events and cardiovascular events (HR 1.61; 95% CI 1.17–2.22) and mortality (HR 1.61, CI 1.17–2.22).
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• Karter AJ, Moffet HH, Liu JY, Lipska KJ. Surveillance of hypoglycemia—limitations of emergency department and hospital utilization data. JAMA Intern Med. 2018. https://doi.org/10.1001/jamainternmed.2018.1014. This study demonstrated that only 5% of severe hypoglycemic events experienced by patients with diabetes culminate in an emergency department visit or hospitalization event.
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• Elliott L, Fidler C, Ditchfield A, et al. Hypoglycemia event rates: a comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. Diabetes Ther. 2016;7(1):45–60. This structured literature review directly compares the rates of hypoglycemia among insulin-treated adults with type 1 and type 2 diabetes as reported in randomized controlled trials (RCTs) and real-world data (RWD). For patients with type 2 diabetes, rates of severe, non-severe, and nocturnal events were all higher in studies relying on RWD, though the differences were much lower than those for patients with type 1 diabetes. This reinforces the importance of using real-world estimates to understand hypoglycemia risk and counsel patients about risks and benefits of glucose-lowering therapy.
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• McCoy RG, Lipska KJ, Herrin J, Jeffery MM, Krumholz HM, Shah ND. Hospital readmissions among commercially insured and Medicare Advantage beneficiaries with diabetes and the impact of severe hypoglycemic and hyperglycemic events. J Gen Intern Med. 2017;32(10):1097–105. https://doi.org/10.1007/s11606-017-4095-x. This study analyzed 594,146 hospitalizations among commercially insured and Medicare Advantage beneficiaries with diabetes between 2009 and 2014 and found that 1.3% of all hospitalizations were for the primary diagnosis of hypoglycemia. This is the first study to place hospitalizations for hypoglycemia and hyperglycemia in the context of all hospitalizations among adults with diabetes in the USA.
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•• Emral R, Pathan F, Cortes CAY, et al. Self-reported hypoglycemia in insulin-treated patients with diabetes: results from an international survey on 7289 patients from nine countries. Diabetes Res Clin Pract. 2017;134:17–28. The International Operations HAT (IO HAT) study retrospectively and prospectively assessed the incidence of hypoglycemia among adults with insulin-treated diabetes (type 1 and type 2) in nine countries (Bangladesh, Colombia, Egypt, Indonesia, Philippines, Singapore, South Africa, Turkey, and United Arab Emirates) and highlighted the discrepancy between prospectively and retrospectively reported rates. Hypoglycemia was retrospectively reported by patients with type 2 diabetes at the rate of 1.6 event/patient/month and prospectively identified at the rate of 2.4 events/patient/month, while hospitalizations for hypoglycemia occurred at the rate of 0.026 event/patient/month.
Levy JC, Davies MJ, Holman RR. Continuous glucose monitoring detected hypoglycaemia in the Treating to Target in Type 2 Diabetes Trial (4-T). Diabetes Res Clin Pract. 2017;131:161–8. https://doi.org/10.1016/j.diabres.2017.01.022.
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Brož J, Brabec M, Žďárská DJ, Fedáková Z, Hoskovcová L, You JY, et al. Fear of driving license withdrawal in patients with insulin-treated diabetes mellitus negatively influences their decision to report severe hypoglycemic events to physicians. Patient Prefer Adherence. 2015;9:1367.
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Douros A, Yin H, Yu O, H Y, et al. Pharmacologic differences of sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events. Diabetes Care. 2017;40(11):1506–13. https://doi.org/10.2337/dc17-0595.
•• Karter AJ, Warton EM, Lipska KJ, et al. Development and validation of a tool to identify patients with type 2 diabetes at high risk of hypoglycemia-related emergency department or hospital use. JAMA Intern Med. 2017;177(10):1461–70. In this study, Karter and colleagues develop and validate in three different healthcare delivery systems an efficient risk model predicting the 12-month risk of hospitalization or emergency department visit for hypoglycemia for adults with type 2 diabetes. This model stratifies patients as being at high (>5%), intermediate (1–5%), or low (<1%) risk of hypoglycemia utilization events based on six variables: total number of prior hypoglycemia-related hospitalization or emergency department visits, total number of emergency department visits for any cause in the past year, insulin use, sulfonylurea use, presence of stage 4 and 5 chronic kidney disease, and age ≥77 years.
•• Schloot NC, Haupt A, Schutt M, et al. Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: how big is the problem? Which patients are at risk? Diabetes Metab Res Rev. 2016;32(3):316–24. Schloot et al. studied a large population of sulfonylurea-treated patients in a real-life setting. They reported an event rate of severe hypoglycemia of 3.9 per 100 patient-years, identifying several key risk factors associated with hypoglycemia, including lack of diabetes education, older age, and impaired kidney function.
Persson F, Nystrom T, Jorgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20(2):344–351. https://doi.org/10.1111/dom.13077.
•• Lipska KJ, Yao X, Herrin J, et al. Trends in drug utilization, glycemic control, and rates of severe hypoglycemia, 2006-2013. Diabetes Care. 2017;40(4):468–75. This study examined the contemporaneous trends in the pharmacological management of type 2 diabetes, glycemic control, and rates of hospitalizations and emergency department visits for severe hypoglycemia among 1.66 million U.S. adults. Lipska et al found that despite the increasing use of GLP-1 receptor agonists and DPP-4 inhibitors, which are associated with a lower risk of hypoglycemia, the overall rates of severe hypoglycemia did not change between 2006 and 2013 (1.3 event/100 person-years). Hypoglycemia rates were highest among the elderly, those with multiple comorbidities, and those with insulin/sulfonylurea use. Glycemic control improved over time in the elderly but worsened in younger and healthier patients.
•• Pathak RD, Schroeder EB, Seaquist ER, Zeng C, Lafata JE, Thomas A, et al. Severe hypoglycemia requiring medical intervention in a large cohort of adults with diabetes receiving care in U.S. Integrated Health Care Delivery Systems: 2005-2011. Diabetes Care. 2016;39(3):363–70. https://doi.org/10.2337/dc15-0858. This study examined the prevalence of severe hypoglycemia requiring emergency department care or hospitalization among 917,440 adults with diabetes (not separated by diabetes type) within a large integrated healthcare delivery system in the USA between 2005 and 2011. Annual rates of severe hypoglycemia ranged from 1.4 to 1.6/100 person-years and were higher among older patients; patients treated with insulin, sulfonylurea, and beta-blockers; and patients with chronic kidney disease, heart failure, cardiovascular disease, depression, and higher HbA1c.
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•• McCoy RG, Lipska KJ, Yao X, Ross JS, Montori VM, Shah ND. Intensive treatment and severe hypoglycemia among adults with type 2 diabetes mellitus: a population-based study. JAMA Intern Med. 2016;176(7):969–78. https://doi.org/10.1001/jamainternmed.2016.2275. This study quantified the prevalence of diabetes overtreatment among commercially insured and Medicare Advantage beneficiaries with non-insulin-requiring type 2 diabetes across the USA and established the association between overtreatment and severe hypoglycemia. McCoy et al found that 18.7% of clinically complex and 26.5% of non-clinically complex patients were potentially overtreated, which increased the risk-adjusted probability of severe hypoglycemia among clinically complex patients from 1.7% over 2 years to 3.0%. Non-clinically complex patients were able to tolerate potential overtreatment without a significant increase in hypoglycemia risk (1.02 versus 1.30% over 2 years).
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Seligman HK, Davis TC, Schillinger D, Wolf MS. Food insecurity is associated with hypoglycemia and poor diabetes self-management in a low-income sample with diabetes. J Health Care Poor Underserved. 2010;21(4):1227–33. https://doi.org/10.1353/hpu.2010.0921.
•• Basu S, Berkowitz SA, Seligman H. The monthly cycle of hypoglycemia: an observational claims-based study of emergency room visits, hospital admissions, and costs in a commercially insured population. Med Care. 2017;55(7):639–45. https://doi.org/10.1097/MLR.0000000000000728. In this nationwide U.S. study conducted among commercially insured adults in the USA, Basu and colleagues demonstrated the association between household income and risk of hypoglycemia-related emergency department visits and hospitalizations, thereby highlighting the potential impact of food insecurity even among insured adults. Patients with household incomes below the national median had a higher rate of severe hypoglycemia overall (203.4 vs. 149.6 events/100,000 person-years), and this risk rose further in the last week of the month, compared to patients with higher household incomes whose hypoglycemia risk remained constant over the course of each month. Moreover, this rise in hypoglycemia among lower-income patients was mitigated by an increase in federal nutrition program benefits, demonstrating how social service/support interventions can help reduce hypoglycemia risk and improve health.
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Aldasouqi S, Sheikh A, Klosterman P, Kniestedt S, Schubert L, Danker R, et al. Hypoglycemia in patients with diabetes who are fasting for laboratory blood tests: the Cape Girardeau Hypoglycemia En Route Prevention Program. Postgrad Med. 2013;125(1):136–43. https://doi.org/10.3810/pgm.2013.01.2629.
Halimi S, Levy M, Huet D, et al. Experience with vildagliptin in type 2 diabetic patients fasting during Ramadan in France: insights from the VERDI Study. Diabetes Ther. 2013;4(2):385–98.
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Vimalananda VG, DeSotto K, Chen T, Mullakary J, Schlosser J, Archambeault C, et al. A quality improvement program to reduce potential overtreatment of diabetes among veterans at high risk of hypoglycemia. Diabetes Spectr. 2017;30(3):211–6. https://doi.org/10.2337/ds16-0006.
•• Schroeder EB, Xu S, Goodrich GK, Nichols GA, O’Connor PJ, Steiner JF. Predicting the 6-month risk of severe hypoglycemia among adults with diabetes: development and external validation of a prediction model. J Diabetes Complicat. 2017;31(7):1158–63. https://doi.org/10.1016/j.jdiacomp.2017.04.004. In this study, Schroeder and colleagues develop and validate two different healthcare delivery systems that are different from Karter et al. (2017) and two risk models predicting the 6-month risk of hospitalization or emergency department visit for hypoglycemia for adults with diabetes (did not differentiate by diabetes type). The full model, which included 16 variables, slightly outperformed the simplified model with six variables. The full model was comprised of patient age, race/ethnicity, diabetes type (type 1 or 2), body mass index, HbA
, estimated glomerular filtration rate (eGFR), any hospitalization in the past year, any emergency department visit in the past year, severe hypoglycemic event in the past year, retinopathy, cardiovascular disease, depression, heart failure, insulin, metformin, and number of classes of glucose-lowering medications. The simplified model was comprised of patient age, diabetes type, HbA
, eGFR, history of a hypoglycemic event in the prior year, and insulin use.
• Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Liberating A1C goals in older adults may not protect against the risk of hypoglycemia. J Diabetes Complicat. 2017;31(7):1197–9. https://doi.org/10.1016/j.jdiacomp.2017.02.014. While diabetes management guidelines and expert consensus recommend that glycemic targets of patients at high risk of hypoglycemia be relaxed in order to prevent future hypoglycemic events, this study demonstrates that such an approach may not be sufficient. In this prospective study, the frequency of hypoglycemic events was monitored by continuous glucose monitoring (CGM) among older adults treated with multiple daily insulin injections or basal insulin with non-insulin agents who had different HbA
1c treatment targets. The duration of hypoglycemia was not different between the HbA
1c groups, regardless of treatment intensity, demonstrating that higher HbA
1c goals may not protect against hypoglycemia.
Munshi MN, Segal AR, Suhl E, et al. Frequent hypoglycemia among elderly patients with poor glycemic control. Arch Intern Med. 2011;171(4):362–4.
•• Sussman JB, Kerr EA, Saini SD, Holleman RG, Klamerus ML, Min LC, et al. Rates of deintensification of blood pressure and glycemic medication treatment based on levels of control and life expectancy in older patients with diabetes mellitus. JAMA Intern Med. 2015;175(12):1942–9. https://doi.org/10.1001/jamainternmed.2015.5110. This study demonstrates that de-intensification of potentially overtreated older adults with diabetes does not occur often in routine clinical practice (this study was conducted in the U.S. Veterans Health Administration), but when it does, treatment de-intensification is safe as it does not result in a clinically significant or concerning rise in HbA
. Glucose-lowering therapy was de-intensified among 27% of patients with HbA
1c <6.0%, 21% of patients with HbA
1c 6.0–6.4%, and 18% of patients with HbA
1c ≥6.5%, demonstrating the remaining opportunities for individualizing and improving the diabetes care among older adults at risk of hypoglycemia.
• Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Simplification of insulin regimen in older adults and risk of hypoglycemia. JAMA Intern Med. 2016;176(7):1023–5. https://doi.org/10.1001/jamainternmed.2016.2288. In this single-arm intervention study, Munshi and colleagues simplified insulin regimens of 65 older adults with type 2 diabetes who, at baseline, were treated with ≥2 insulin injections per day or with any hypoglycemia on baseline 5-day continuous glucose monitor assessment. Simplification to basal insulin with or without non-insulin agents resulted in reduction in hypoglycemia, reduction in diabetes distress symptoms, reduction in HbA
1c among patients with baseline HbA
1c ≥8%, and slight increase in HbA
1c among patients with baseline HbA
1c <7.0%. This demonstrates the importance of treatment simplification and de-intensification among older adults not only to reduce hypoglycemia but also to improve quality of life and attain safe glycemic targets appropriate for patient age.
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